tbuckley/cabot-search huggingface dataset:
Abstract B001: Inverse relationship between tissue fusobacterium nucleatum amount and CD274 (PD-L1) expression of colorectal carcinoma
Authors: Tomotaka Ugai, Takashi Shimizu, Hidetaka Kawamura, Yasutoshi Takashima, Juha P. Väyrynen, Seyed Mostafa Mousavi Kahaki, Kazuo Okadome, Yohei Masugi, Annacarolina da Silva, Xuehong Zhang, Andrew T. Chan, Molin Wang, Jeffrey A. Meyerhardt, Jonathan A. Nowak, Mingyang Song, Marios Giannakis, Shuji Ogino
Journal: Cancer Research (2022)

Abstract Background: The CD274 (programmed cell death ligand 1, PD-L1)/PDCD1 (programmed cell death 1, PD-1) immune checkpoint axis is known to regulate the antitumor immune response. Evidence suggests that Fusobacterium nucleatum (F. nucleatum) promotes colorectal carcinogenesis through its suppressive effect on antitumor immunity. We hypothesized that tumor CD274 overexpression and intratumor abundance of F. nucleatum might tend to be mutually exclusive immune evasion mechanisms in colorectal cancer. Methods: We assessed tumor CD274 expression by immunohistochemistry and F. nucleatum DNA within tumor tissue by quantitative polymerase chain reaction in 812 cases among 4,465 incident colorectal cancer cases that had occurred in the Nurses’ Health Study and the Health Professionals Follow-up Study. To adjust for potential confounders and selection bias due to tissue data availability, inverse probability weighting was integrated into multivariable ordinal logistic regression analyses to examine the association of tumor CD274 expression with the amount of intratumor F. nucleatum. Results: Tumor CD274 expression was negative in 93 (11%), low in 231 (28%), intermediate in 210 (26%), and high in 278 (34%) of 812 cases. F. nucleatum DNA was detected in tumor tissue in 109 (13%) cases of 812 cases. Tumor CD274 expression level was inversely associated with the amount of F. nucleatum in colorectal cancer tissue. For one category increase in three ordinal F. nucleatum categories (negative, low, and high), multivariable-adjusted odds ratios (with 95% confidence intervals) of the low, middle, and high CD274 expression categories (vs. negative) were 0.78 (0.41-1.51), 0.64 (0.32-1.28), and 0.50 (0.25–0.99), respectively (Ptrend=0.032). Conclusions: We found that CD274 expression was inversely associated with the amount of F. nucleatum in colorectal cancer tissue. Our findings suggest that a colorectal tumor tends to have either of the immune evasion mechanisms, i.e., PDCD1 (PD-1) immune checkpoint activation and intratumor abundance of F. nucleatum. Citation Format: Tomotaka Ugai, Takashi Shimizu, Hidetaka Kawamura, Yasutoshi Takashima, Juha P. Väyrynen, Seyed Mostafa Mousavi Kahaki, Kazuo Okadome, Yohei Masugi, Annacarolina da Silva, Xuehong Zhang, Andrew T. Chan, Molin Wang, Jeffrey A. Meyerhardt, Jonathan A. Nowak, Mingyang Song, Marios Giannakis, Shuji Ogino. Inverse relationship between tissue fusobacterium nucleatum amount and CD274 (PD-L1) expression of colorectal carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B001.
Abstract A004: Molecular adenoma features to predict metachronous colorectal cancer risk: A nested-case control study
Authors: Henriette C. Jodal, Eddymurphy U. Akwiwu, Leticia G. Leon, Margriet Lemmens, Pien Delis-van Diemen, Dagmar Klotz, Meike de Wit, Remond Fijneman, Monique van Leerdam, Evelien Dekker, Manon C. W. Spaander, Gerrit A. Meijer, Michael Bretthauer, Magnus Løberg, Veerle M. H. Coupé, Mette Kalager, Beatriz Carvalho
Journal: Cancer Research (2022)

Abstract Introduction: In colorectal cancer (CRC) surveillance, adenoma characteristics such as size, number of adenomas, dysplasia, and villous components, are used as indicators for risk of developing metachronous cancer and guide the surveillance interval. The current risk groups (e.g., advanced adenomas) cannot optimally distinguish high risk from low risk, which may result in suboptimal surveillance strategies. Specific DNA copy number aberrations are associated with risk of colorectal adenoma-to-carcinoma progression, but these aberrations are present in only a subset of advanced adenomas. Therefore, we hypothesize that specific DNA copy number aberrations may better predict the risk of CRC than advanced adenoma. Aim: To evaluate whether a molecularly-defined high-risk adenoma is a better risk factor for CRC than the presently used advanced adenoma. Materials and methods: DNA copy number profiles were determined, by means of low-coverage whole genome sequencing, on a series of 529 adenomas, selected from a Norwegian adenoma cohort. We retrieved detailed information on adenoma characteristics and whether adenoma patients were subsequently diagnosed with CRC or not. By univariate and multivariate regression analysis we estimated the odds ratio for association between the development of CRC and baseline presence of advanced adenoma versus presence of a molecularly-defined high-risk adenoma, respectively. Results: Molecular high-risk features were observed in 85/267 (32%) of advanced adenomas and in 27/262 (10%) of non-advanced adenomas. The odds ratio for developing metachronous CRC was 3.58 (p=2.84E-8) and 1.90 (p=0.012), when an advanced adenoma or molecular high-risk adenoma was detected at the baseline colonoscopy, respectively. In the multivariate regression analysis only advanced adenoma was as a significant risk factor for CRC. Conclusion: Molecularly-defined high-risk adenomas are associated with an increased risk of CRC. However, the advanced adenoma is a stronger predictor for risk of CRC. Citation Format: Henriette C. Jodal, Eddymurphy U. Akwiwu, Leticia G. Leon, Margriet Lemmens, Pien Delis-van Diemen, Dagmar Klotz, Meike de Wit, Remond Fijneman, Monique van Leerdam, Evelien Dekker, Manon C. W. Spaander, Gerrit A. Meijer, Michael Bretthauer, Magnus Løberg, Veerle M. H. Coupé, Mette Kalager, Beatriz Carvalho. Molecular adenoma features to predict metachronous colorectal cancer risk: A nested-case control study [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A004.
Abstract IA012: Risk factors for early-onset colorectal cancer
Authors: Richard B. Hayes
Journal: Cancer Research (2022)

Abstract Colorectal cancer (CRC) incidence has been declining in the U.S. overall; however, the incidence of CRC in individuals less than 50 years of age (early-onset disease) has been increasing over the last several decades in the U.S. and elsewhere. Furthermore, cancers diagnosed in people less than 50 years of age tend to be characterized by advanced stage and greater propensity for recurrence, increasing the urgency of this emerging public health problem. Responding to the rapid rise in early-onset CRC, some CRC screening guidelines have changed to lower the screening age from 50 to 45, for average risk individuals. Our purpose was to identify genetic, environmental and lifestyle risk factors for early-onset CRC which could be used in predictive modelling to identify the younger individuals who would most benefit from screening. This research, which included more than 3,500 early-onset CRC and 3,500 comparison controls, serves to comprehensively assess genetic, environmental and lifestyle risks in early-onset CRC, as well as to develop a risk prediction tool specifically for this age group. We found that a polygenic risk score is associated with early-onset CRC, particularly for those without a family history of CRC. Several known CRC environmental and lifestyle risk factors are also linked with early-onset disease. In summary, the absolute risk for CRC in young people is low; however, genetic, environmental and lifestyle information provides initial stratification into low and high-risk groups. These findings may contribute to the identification of individuals susceptible to early-onset CRC for tailored early detection or other preventive interventions. Citation Format: Richard B. Hayes. Risk factors for early-onset colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA012.
Abstract A034: Cancer and immunology: The homeostasis dance
Authors: Bene Akromaa Ekine-Afolabi
Journal: Cancer Research (2022)

Abstract The human body is made up of not only tissues and blood, but also present are microbiota on surfaces of the skin, mucosal membrane of the intestine, urogenital, lungs, and mouth, to form ecological niches. Some of these niches have been well studied, while some are yet to be elucidated due to the unknown presence of these microbiota in such system. T cell response by immune system is one step of the cancer-immunity cycle, that maintains the prevention of autoimmunity. Cancer cells have T cell inhibitory signals including PD-L1 which have been identified for the development of new immunotherapy that are specifically responsible for hindering immune effector inhibition, thereby reinvigorating, and enhancing pre-existing anticancer immune response. Previous activity in immune therapies have always considered suppressive factors in the tumor microenvironment without consideration to other factors such as the genetic basis of the immune system. Attention to the immune system has always been on the response to the pathogens, or the threatening foreign target, but not on the genes responsible for regulating the immune system. The immune system is a concert of interactions between existing microbes and host. One of the major tools of cellular interaction is epigenetics. Epigenetic information regulates differentiation and development, thus can impact on pathological condition. Therefore, epigenetics interaction between microbes and host is vital in cancer development and treatment. Diagnostic and prognosis will be impacted by the understanding of the interactions between microbes and host, thereby informing on precision medicine. Citation Format: Bene Akromaa Ekine-Afolabi. Cancer and immunology: The homeostasis dance [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A034.
Abstract IA006: The effect of ancestry and the genomics of colorectal cancer: Implications on incidence and outcomes
Authors: Parvathi A. Myer
Journal: Cancer Research (2022)

Abstract Blacks have a higher incidence of colorectal cancer (CRC) and worse survival rates when compared to Whites. Comprehensive genomic profiling was performed in 46,140 colorectal adenocarcinoma cases. Ancestry-informative markers identified 5,301 patients of African descent (AFR) and 33,770 patients of European descent (EUR). AFR were younger, had fewer MSI-H tumors, and had significantly more frequent alterations in KRAS, APC, and PIK3CA. AFR had increased frequency of KRAS mutations specifically KRAS G12D and KRAS G13. There were no differences in rates of actionable kinase driver alterations (HER2, MET, NTRK, ALK, ROS1, RET). In patients with young onset CRC (&amp;lt;50 years), AFR and EUR had similar frequency of MSI-H and TMB-H tumors, and strikingly different trends in APC mutations by age, as well as differences in MAPK pathway alterations. These findings inform treatment decisions, impact prognosis, and underscore the need for model systems representative of our diverse US population. Further studies are needed to investigate the role of colon polyps and the effect of genomics, ancestry and social determinants of health on CRC incidence and outcomes. Citation Format: Parvathi A. Myer. The effect of ancestry and the genomics of colorectal cancer: Implications on incidence and outcomes [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA006.
Abstract B014: Genotype-tailored ERK/MAPK pathway and HDAC inhibition rewires the apoptotic rheostat to trigger colorectal cancer cell death
Authors: Laura J. Jenkins, Ian Y. Luk, Walter D. Fairlie, Erinna F. Lee, Michelle Palmieri, Kael L. Schoffer, Tao Tan, Irvin Ng, Natalia Vukelic, Sharon Tran, Janson Tse, Rebecca Nightingale, Zakia Alam, Fiona Chionh, George Iatropoulos, Matthias Ernst, Shoukat Afshar-Sterle, Jayesh Desai, Peter Gibbs, Oliver M. Sieber, Amardeep S. Dhillon, Niall C. Tebbutt, John M. Mariadason
Journal: Cancer Research (2022)

Abstract The EGFR/RAS/MEK/ERK signaling pathway (ERK/MAPK) is hyper-activated in most colorectal cancers (CRCs). A current limitation of inhibitors of this pathway is that they primarily induce cytostatic effects in CRC cells. Nevertheless, these drugs do induce expression of pro-apoptotic factors, suggesting they may prime CRC cells to undergo apoptosis. As histone deacetylase inhibitors (HDACi) induce expression of multiple pro-apoptotic proteins, we examined whether they could synergize with ERK/MAPK inhibitors to trigger CRC cell apoptosis. Combined MEK/ERK and HDAC inhibition synergistically induced apoptosis in CRC cell lines and patient-derived tumor organoids in vitro,and attenuated Apc-initiated adenoma formation in vivo. Mechanistically, combined MAPK/HDAC inhibition enhanced expression of the BH3-only pro-apoptotic proteins BIM and BMF, and their knockdown significantly attenuated MAPK/HDAC inhibitor-induced apoptosis. Importantly, we demonstrate that the paradigm of combined MAPK/HDAC inhibitor treatment to induce apoptosis can be tailored to specific MAPK genotypes in CRCs, by combining a HDAC inhibitor with either an EGFR, KRASG12C or BRAFV600 inhibitor in KRAS/BRAFWT ; KRASG12C , BRAFV600E CRC cell lines respectively. These findings identify a series of ERK/MAPK genotype tailored treatment strategies that can readily undergo clinical testing for the treatment of colorectal cancer. Citation Format: Laura J. Jenkins, Ian Y. Luk, Walter D. Fairlie, Erinna F. Lee, Michelle Palmieri, Kael L. Schoffer, Tao Tan, Irvin Ng, Natalia Vukelic, Sharon Tran, Janson Tse, Rebecca Nightingale, Zakia Alam, Fiona Chionh, George Iatropoulos, Matthias Ernst, Shoukat Afshar-Sterle, Jayesh Desai, Peter Gibbs, Oliver M. Sieber, Amardeep S. Dhillon, Niall C. Tebbutt, John M. Mariadason. Genotype-tailored ERK/MAPK pathway and HDAC inhibition rewires the apoptotic rheostat to trigger colorectal cancer cell death [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B014.
Abstract A001: The development of a multilevel risk prediction model to identify risk of failure to complete CRC screening
Authors: Amanda F. Petrik
Journal: Cancer Research (2022)

Abstract Context: The use of predictive analytics can help health systems target the right services to the right patients at the right time while improving population health. Multilevel data, or data at the interpersonal, organizational, community, and policy levels, is rarely sought after but may be used to improve risk prediction by providing information about a patient and the many groups to which they belong. Colorectal cancer screening promotion can be expensive and not all patients need it. Objective: This study sought to develop a risk prediction model using individual data available in the EHR, and then compared a multilevel risk prediction model using publicly available multilevel data. Study design and analysis: Retrospective data was used to develop a risk model, using logistic regression, first in data available in the EHR, and then adding multilevel data. Setting or dataset: This retrospective data only study was conducted at Kaiser Permanente Northwest. Population studied: Patients were eligible who were 50-75 years old, had been members at KPNW for at least a year before their birthday in 2018, and if they were due for screening. Results: The individual level model was sufficient and included 14 characteristics, and had a bootstrap corrected C-statistic of 0.722. The multilevel model added 9 variables, and the bootstrap corrected C-statistic was 0.724. Conclusions: Models can be used to identify patients unlikely to screen, although the performance of the model after adding multilevel data did not improve. Screening models could help in population health management of CRC screening. Citation Format: Amanda F. Petrik. The development of a multilevel risk prediction model to identify risk of failure to complete CRC screening [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A001.
Abstract IA013: Early-onset colorectal cancer: Emerging risk factors and early detection
Authors: Yin Cao
Journal: Cancer Research (2022)

Abstract Early-onset colorectal cancer (CRC) is increasing in the United States and globally. Compared to CRC diagnosed at older ages, patients with early-onset CRC experienced significant diagnostic delays, with tumors of advanced clinicopathological features and unknown etiology. While screening recommendations have been recently lowered to age 45 in the United States, about half of early-onset CRC cases are diagnosed before age 45, thus will not be detected via screening. This presentation will review emerging risk factors of early-onset CRC throughout the life course, as well as clinical signs and symptoms associated with early-onset CRC. Citation Format: Yin Cao. Early-onset colorectal cancer: Emerging risk factors and early detection [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr IA013.
Abstract A014: Identifying and overcoming resistance to RAS targeted therapy in colorectal cancer
Authors: Marie J. Parsons, Maria Zafra, Sukanya Goswami, Maria Teresa Calvo Fernandez, John E. Wilkinson, Lukas E. Dow
Journal: Cancer Research (2022)

Abstract KRAS is the most frequently mutated oncogene in human cancer and a potent oncogenic driver. In colorectal cancer (CRC), pathogenic KRAS mutations are observed in up to 50% of cases, yet there is little understanding of how distinct mutations dictate tumor biology including initiation, progression and therapy response. The recent approval of targeted KRASG12C inhibitors brings promise to transform the therapeutic landscape for many patients who lack effective, personalized treatment. Clinically acquired resistance is already observed, highlighting the need to identify mechanisms of resistance and approaches to overcome them. The aim of this study is to understand how distinct Kras alterations drive tumorigenesis and identify reasons underlying the failure of KRAS inhibitors in CRC. To explore the clinical significance of distinct KRAS mutations in tumor development and therapy response, we used Cre- conditional (Lox- stop- Lox) Kras mutant mouse strains crossed to the colon specific promoter Fabp1-Cre and Apc(flox/flox) mice. In the absence of Apc, we demonstrated that distinct Kras mutations G12C and G13D drive unique phenotypes in the colon which demonstrates that subtle mutational changes can dramatically alter the physiological response in vivo, and make distinct KRAS alleles an attractive target for targeted therapeutics. In tumor bearing models of CRC, we observed that KrasG12D drives large numbers of smaller tumors, while KrasG13D drives smaller numbers of larger tumors. To investigate the differences observed in tumorigenesis, we are studying the potential role of Kras to prime the colon for APC loss and the consequences of Kras alterations on the stem cell dynamics in driving tumorigenesis. Further, we employed our unique LSL-Kras mutant mouse strains and colon derived organoids to assess the therapeutic response of G12C and pan Kras inhibitors alone or in combination with upstream target drugs including inhibitors targeting EGFR signaling (EGFR, SHP2, SOS1 and MEK) and the Wnt signaling pathway. Together, this work has identified that distinct mutations in KRAS creates colon cancer specific vulnerabilities which dictates tumor biology. The unique in vivo and ex vivo organoid models provide an ideal platform to identify the underlying cause of failure of G12C inhibitors and developing effective approaches to target RAS in CRC. Citation Format: Marie J. Parsons, Maria Zafra, Sukanya Goswami, Maria Teresa Calvo Fernandez, John E. Wilkinson, Lukas E. Dow. Identifying and overcoming resistance to RAS targeted therapy in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A014.
Abstract B030: Dipeptidase-1 is a highly upregulated protein in CRC exosomes: Potential clinical relevance
Authors: Matthew E. Bechard, Sarah E. Glass, Robert J. Coffey
Journal: Cancer Research (2022)

Abstract Bert Vogelstein and co-workers identified DPEP1 in 2001 as one of the top six upregulated genes encoding a membrane or secreted protein in colorectal adenomas and cancers (CRCs). DPEP1 is a GPI-linked, zinc-dependent dipeptidase whose enzymatic activity includes processing extracellular glutathione and converting LTD4 to LTE4. Recently, it was reported to act nonenzymatically as a receptor for neutrophils on liver and lung endothelial cells and to influence monocyte migration. DPEP1 has been reported to have roles in cancer proliferation, invasion and metastasis. We recently showed that DPEP1 is the most abundant protein in small extracellular vesicles (sEVs) released from CRC cell lines by mass spectrometry and is present in a subset of EGFR+/CD81+ exosomes along with other clinically relevant biomarkers by fluorescence-activated vesicle sorting (FAVS) (Q Zhang et al., Nature Cell Biology 23:1240-1254, 2021). We also found that DPEP1/CEACAM5 double-positive exosomes are increased in the plasma from three CRC patients compared to normal controls. Immunohistochemical staining for DPEP1 in clinically well-annotated adenoma and CRC tissue microarrays has revealed staining in 27% of adenomas and 71% of CRCs, whereas no staining was observed in normal colonic tissue. Moreover, diffuse cytoplasmic staining in CRCs was associated with a worse progression-free and overall survival. We have now generated adenoma organoids, some of which express endogenous DPEP1 that localizes to the apical plasma membrane in 3D organoids and when cultured as polarized monolayers on Transwell filters. We plan to examine the bi-directional effects of cellular DPEP1 and DPEP1-containing EVs and freshly isolated neutrophils and/or their EVs in a co-culture system that is part of our recently funded Translational and Biological Science in Early Lesions (TBEL) NCI U54 grant. Citation Format: Matthew E. Bechard, Sarah E. Glass, Robert J. Coffey. Dipeptidase-1 is a highly upregulated protein in CRC exosomes: Potential clinical relevance [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr B030.